Severe acute respiratory distress syndrome (ARDS) occurs in approximately 10% of patients entering the intensive care unit, affecting nearly 190,000 patients per year in the US alone. The initiation of ARDS is multifactorial but often results in an inability to oxygenate the patient using conventional ventilation methods. Despite the use of different ventilator modes and various inhalational agents, patient proning etc., approximately 30-50% of ARDS cases end in mortality. The ultimate aim of pulmonary support is to cause the least damage to the lung parenchyma while it heals; with this in mind, extracorporeal membrane oxygenation (ECMO) has been used in the most severe cases, when other means have failed. Unfortunately, ECMO also has a substantial contraindication list and risk profile, which in part is driven by the need for full anticoagulation while the patient is on the circuit. For a large portion of patients ? traumatically injured patients, in particular ? full anticoagulation carries the risk of uncontrolled hemorrhage in the brain or other organs affected by trauma. We therefore continue to search for effective means of resting the lungs while supporting the oxygenation and ventilation needs of the patient. Oxygen microbubbles (OMBs) have shown promise as a method of extra-pulmonary oxygenation that is safe, versatile and does not require use of anticoagulants. Our work is innovative as it explores a novel method for extra-pulmonary oxygenation using body cavities, such as the peritoneal cavity. This could have a significant impact on the field of trauma care in situations where anticoagulants cannot be used, as well as in settings where ECMO technology is not readily accessible or practical. We have shown in small-animal models of ARDS induced by lipopolysaccharide (LPS) and smoke inhalation (SI) that an intraperitoneal injection of OMBs improves peripheral oxygenation saturation by 10-15% to normoxic levels, as well as survival and lung health. While our preliminary studies have shown favorable improvements in oxygenation and survival in a preliminary lipid-based formulation, it is unclear that this chemistry is the optimal formulation for intraperitoneal delivery. The goal of this research project is to develop, characterize and test alternative OMB formulations based on different lipids, lung surfactant, protein and sugar shells. The first aim will determine pharmacokinetic parameters for novel OMB formulations. We will perform a ?deep dive? design analysis of four different shell types: characterizing mass transfer properties, gas-exchange phenomena and in vivo persistence in the peritoneal cavity. The second aim will use a novel electrode-phosphorescence method to measure OMB dose response and effects on muscle microvascular O2 supply in local tissue. The third aim will test the new OMB formulations in rodent and pig models of LPS-ARDS. Finally, the fourth aim will Test new OMB formulations in rodent and pig models of SI-ARDS. Overall, this research will test safety and efficacy of peritoneal microbubble oxygenation in small and large animal models of ARDS, as well as establish key engineering principles for rational design of oxygen microbubbles for peritoneal oxygenation.